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Journal For Immunotherapy of Cancer May 2021Checkpoint inhibitors targeting programmed death receptor-1 (PD-1) have been tested in the neoadjuvant setting for the treatment of locoregionally advanced head and neck...
Neoadjuvant immunoradiotherapy results in high rate of complete pathological response and clinical to pathological downstaging in locally advanced head and neck squamous cell carcinoma.
BACKGROUND
Checkpoint inhibitors targeting programmed death receptor-1 (PD-1) have been tested in the neoadjuvant setting for the treatment of locoregionally advanced head and neck squamous cell carcinoma (HNSCC); however, response rates are modest. We hypothesized that adding stereotactic body radiation therapy (SBRT) to anti-PD-1 would be safe prior to definitive surgical resection and would enhance pathological response compared with historical cohorts of patients with locoregionally advanced HNSCC treated with checkpoint inhibitor alone.
METHODS
The Neoadjuvant Immuno-Radiotherapy Trial was an investigator-initiated single institution phase Ib clinical trial that enrolled patients with previously untreated locally advanced HPV-positive and HPV-negative HNSCC between 2018 and 2019. Eligible patients were treated with neoadjuvant SBRT at a total dose of either 40 Gy in 5 fractions or 24 Gy in 3 fractions, delivered in a 1-week timespan, with or without nivolumab, prior to definitive surgical resection. Patients were then planned for treatment with adjuvant nivolumab for 3 months. The primary safety endpoint was unplanned delay in surgery considered to be at least possibly related to neoadjuvant treatment. The primary efficacy endpoints included pathological complete response (pCR), major pathological response (mPR), and the rate of clinical to pathological downstaging after neoadjuvant treatment.
RESULTS
Twenty-one patients underwent neoadjuvant treatment, which was well tolerated and did not delay surgery, thus meeting the primary endpoint. Tissue responses were characterized by robust inflammatory infiltrates in the regression bed, plasma cells and cholesterol clefts. Among the entire study group, the mPR and pCR rate was 86% and 67%, respectively. Clinical to pathological downstaging occurred in 90% of the patients treated.
CONCLUSION
These data demonstrate that radiation delivered only to the gross tumor volume combined with immunotherapy was safe, resulted in a high rate of mPR and should be further evaluated as a locally focused neoadjuvant therapy for patients with head and neck cancer.
TRIAL REGISTRATION NUMBER
This study is registered with clinicaltrials.gov (NCT03247712) and is active, but closed to patient accrual.
Topics: Aged; Dose Fractionation, Radiation; Female; Head and Neck Neoplasms; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Nivolumab; Oregon; Programmed Cell Death 1 Receptor; Radiosurgery; Radiotherapy, Adjuvant; Squamous Cell Carcinoma of Head and Neck; Time Factors; Treatment Outcome
PubMed: 33963014
DOI: 10.1136/jitc-2021-002485 -
Reports of Practical Oncology and... 2022This paper describes how to select the most appropriate stereotactic radiotherapy (SRT ) dose and fractionation scheme according to lesion size and site, organs at risk... (Review)
Review
This paper describes how to select the most appropriate stereotactic radiotherapy (SRT ) dose and fractionation scheme according to lesion size and site, organs at risk (OARs) proximity and the biological effective dose. In single-dose SRT, 15-34 Gy are generally used while in fractionated SRT 30 and 75 Gy in 2-5 fractions are administered. The ICRU Report No. 91, which is specifically dedicated to SRT treatments, provided indications for dose prescription (with its definition and essential steps), dose delivery and optimal coverage which was defined as the best planning target volume coverage that can be obtained in the irradiated district. Calculation algorithms and OAR s dose constraints are provided as well as treatment planning system characteristics, suggested beam energy and multileaf collimator leaf size. Finally, parameters for irradiation geometry and plan quality are also reported.
PubMed: 35402033
DOI: 10.5603/RPOR.a2021.0139 -
Frontiers in Oncology 2020During the last years, preclinical and clinical studies have emerged supporting the rationale to integrate radiotherapy and immunotherapy. Radiotherapy may enhance the... (Review)
Review
During the last years, preclinical and clinical studies have emerged supporting the rationale to integrate radiotherapy and immunotherapy. Radiotherapy may enhance the effects of immunotherapy by improving tumor antigen release, antigen presentation, and T-cell infiltration. Recently, magnetic resonance guided radiotherapy (MRgRT) has become clinically available. Compared to conventional radiotherapy techniques, MRgRT firstly allows for daily on-table treatment adaptation, which enables both dose escalation for increasing tumor response and superior sparing of radiosensitive organs-at-risk for reducing toxicity. The current review focuses on the potential of combining MR-guided adaptive radiotherapy with immunotherapy by providing an overview on the current status of MRgRT, latest developments in preclinical and clinical radio-immunotherapy, and the unique opportunities and challenges for MR-guided radio-immunotherapy. MRgRT might especially assist in answering open questions in radio-immunotherapy regarding optimal radiation dose, fractionation, timing of immunotherapy, appropriate irradiation volumes, and response prediction.
PubMed: 33604296
DOI: 10.3389/fonc.2020.615697 -
Reports of Practical Oncology and... 2022Even though systemic therapy is standard treatment for lymph node metastases, metastasis-directed stereotactic radiotherapy (SRT ) seems to be a valid option in... (Review)
Review
Even though systemic therapy is standard treatment for lymph node metastases, metastasis-directed stereotactic radiotherapy (SRT ) seems to be a valid option in oligometastatic patients with a low disease burden. Positron emission tomography-computed tomography (PET-CT ) is the gold standard for assessing metastases to the lymph nodes; co-registration of PET-CT images and planning CT images are the basis for gross tumor volume (GTV ) delineation. Appropriate techniques are needed to overcome target motion. SRT schedules depend on the irradiation site, target volume and dose constraints to the organs at risk (OARs) of toxicity. Although several fractionation schemes were reported, total doses of 48-60 Gy in 4-8 fractions were proposed for mediastinal lymph node SRT, with the spinal cord, esophagus, heart and proximal bronchial tree being the dose limiting OAR s. Total doses ranged from 30 to 45 Gy, with daily fractions of 7-12 Gy for abdominal lymph nodes, with dose limiting OARs being the liver, kidneys, bowel and bladder. SRT on lymph node metastases is safe; late side effects, particularly severe, are rare.
PubMed: 35402021
DOI: 10.5603/RPOR.a2022.0007 -
Predictors of Free Flap Volume Loss in Nonosseous Reconstruction of Head and Neck Oncologic Defects.Ear, Nose, & Throat Journal Jan 2022Free tissue reconstruction of the head and neck must be initially overcorrected due to expected postoperative free flap volume loss, which can be accelerated by adjuvant...
OBJECTIVES
Free tissue reconstruction of the head and neck must be initially overcorrected due to expected postoperative free flap volume loss, which can be accelerated by adjuvant radiation therapy. In this study, we aim to identify patient and treatment-specific factors that may significantly contribute to this phenomenon and translate these characteristics into a predictive model for expected percent free flap volume loss in a given patient.
METHODS
Patients with a history of oral cavity and/or oropharyngeal cancer who underwent nonosseous free flap reconstruction were reviewed between January 2009 and November 2018 at a tertiary care center. Demographics/characteristics, total radiation dose, radiation fractionation (RF), and pre/postradiation free flap volume as evaluated by computed tomography imaging were collected. Free flap volume was measured by a fellowship-trained neuroradiologist in all cases. Only patients receiving adjuvant radiotherapy with available pre/postradiation imaging were included. Multivariable linear regression modeling for prediction of free flap volume loss was performed with optimization via stepwise elimination.
RESULTS
Thirty patients were included for analysis. Mean flap volume loss was 42.7% ± 17.4%. The model predicted flap volume loss in a significant fashion ( = .004, R = 0.49) with a mean magnitude of error of 9.8% ± 7.5%. Age (β = 0.01, = .003) and RF (β = -0.01, = .009) were individual predictors of flap volume loss.
CONCLUSIONS
Our model predicts percent free flap volume loss in a significant fashion. Age and RF are individual predictors of free flap volume loss, the latter being a novel finding that is also modifiable through hyperfractionation radiotherapy schedules.
Topics: Age Factors; Dose Fractionation, Radiation; Female; Free Tissue Flaps; Head and Neck Neoplasms; Humans; Linear Models; Male; Middle Aged; Postoperative Complications; Radiotherapy, Adjuvant; Plastic Surgery Procedures; Risk Factors
PubMed: 32633655
DOI: 10.1177/0145561320938903 -
Radiation Oncology (London, England) Aug 2021Multifocal manifestation of high-grade glioma is a rare disease with very unfavourable prognosis. The pathogenesis of multifocal glioma and pathophysiological...
BACKGROUND
Multifocal manifestation of high-grade glioma is a rare disease with very unfavourable prognosis. The pathogenesis of multifocal glioma and pathophysiological differences to unifocal glioma are not fully understood. The optimal treatment of patients suffering from multifocal high-grade glioma is not defined in the current guidelines, therefore individual case series may be helpful as guidance for clinical decision-making.
METHODS
Patients with multifocal high-grade glioma treated with conventionally fractionated radiation therapy (RT) in our institution with or without concomitant chemotherapy between April 2011 and April 2019 were retrospectively analysed. Multifocality was neuroradiologically assessed and defined as at least two independent contrast-enhancing foci in the MRI T1 contrast-enhanced sequence. IDH mutational status and MGMT methylation status were assessed from histopathology records. GTV, PTV as well as the V30Gy, V45Gy and D2% volumes of the brain were analysed. Overall and progression-free survival were calculated from the diagnosis until death and from start of radiation therapy until diagnosis of progression of disease in MRI for all patients.
RESULTS
20 multifocal glioma cases (18 IDH wild-type glioblastoma cases, one diffuse astrocytic glioma, IDH wild-type case with molecular features of glioblastoma and one anaplastic astrocytoma, IDH wild-type case) were included into the analysis. Resection was performed in two cases and stereotactic biopsy only in 18 cases before the start of radiation therapy. At the start of radiation therapy patients were 61 years old in median (range 42-84 years). Histopathological examination showed IDH wild-type in all cases and MGMT promotor methylation in 11 cases (55%). Prescription schedules were 60 Gy (2 Gy × 30), 59.4 Gy (1.8 Gy × 33), 55 Gy (2.2 Gy × 25) and 50 Gy (2.5 Gy × 20) in 15, three, one and one cases, respectively. Concomitant temozolomide chemotherapy was applied in 16 cases, combined temozolomide/lomustine chemotherapy was applied in one case and concomitant bevacizumab therapy in one case. Median number of GTVs was three. Median volume of the sum of the GTVs was 26 cm. Median volume of the PTV was 425.7 cm and median PTV to brain ratio 32.8 percent. Median D2% of the brain was 61.5 Gy (range 51.2-62.7) and median V30Gy and V45 of the brain were 59.9 percent (range 33-79.7) and 40.7 percent (range 14.9-64.1), respectively. Median survival was eight months (95% KI 3.6-12.4 months) and median progression free survival after initiation of RT five months (95% CI 2.8-7.2 months). Grade 2 toxicities were detected in eight cases and grade 3 toxicities in four cases consisting of increasing edema in three cases and one new-onset seizure. One grade 4 toxicity was detected, which was febrile neutropenia related to concomitant chemotherapy.
CONCLUSION
Conventionally fractionated RT with concomitant chemotherapy could safely be applied in multifocal high-grade glioma in this case series despite large irradiation treatment fields.
Topics: Adult; Aged; Aged, 80 and over; Brain Neoplasms; Chemoradiotherapy; Dose Fractionation, Radiation; Female; Glioma; Humans; Male; Middle Aged; Radiotherapy; Retrospective Studies
PubMed: 34454558
DOI: 10.1186/s13014-021-01886-3 -
Advances in Radiation Oncology 2023Brain metastases are a common development in patients with malignant solid tumors. Stereotactic radiosurgery (SRS) has a long track record of effectively and safely...
PURPOSE
Brain metastases are a common development in patients with malignant solid tumors. Stereotactic radiosurgery (SRS) has a long track record of effectively and safely treating these patients, with some limitations to the use of single fraction SRS based on size and volume. In this study, we reviewed outcomes of patients treated using SRS and fractionated SRS (fSRS) to compare predictors and outcomes of those treatments.
METHODS AND MATERIALS
Two hundred patients treated with SRS or fSRS for intact brain metastases were included. We tabulated baseline characteristics and performed a logistic regression to identify predictors of fSRS. Cox regression was used to identify predictors of survival. Kaplan-Meier analysis was used to calculate survival, local failure, and distant failure rates. A receiver operating characteristic curve was generated to determine timepoint from planning to treatment associated with local failure.
RESULTS
The only predictor of fSRS was tumor volume >2.061 cm. There was no difference in local failure, toxicity, or survival by fractionation of biologically effective dose. Predictors of worse survival were age, extracranial disease, history of whole brain radiation therapy, and volume. Receiver operating characteristic analysis identified 10 days as potential factor in local failure. At 1 year, local control was 96.48 and 76.92% for those patients treated before or after that interval, respectively ( = .0005).
CONCLUSIONS
Fractionated SRS is a safe and effective alternative for patients with larger volume tumors not suitable for single fraction SRS. Care should be taken to treat these patients expeditiously as a delay was shown to affect local control in this study.
PubMed: 36845616
DOI: 10.1016/j.adro.2022.101161 -
Radiation Oncology (London, England) Mar 2021Whole brain radiation (WBRT) may lead to acute xerostomia and dry eye from incidental parotid and lacrimal exposure, respectively. We performed a prospective... (Observational Study)
Observational Study
BACKGROUND
Whole brain radiation (WBRT) may lead to acute xerostomia and dry eye from incidental parotid and lacrimal exposure, respectively. We performed a prospective observational study to assess the incidence/severity of this toxicity. We herein perform a secondary analysis relating parotid and lacrimal dosimetric parameters to normal tissue complication probability (NTCP) rates and associated models.
METHODS
Patients received WBRT to 25-40 Gy in 10-20 fractions using 3D-conformal radiation therapy without prospective delineation of the parotids or lacrimals. Patients completed questionnaires at baseline and 1 month post-WBRT. Xerostomia was assessed using the University of Michigan xerostomia score (scored 0-100, toxicity defined as ≥ 20 pt increase) and xerostomia bother score (scored from 0 to 3, toxicity defined as ≥ 2 pt increase). Dry eye was assessed using the Subjective Evaluation of Symptom of Dryness (SESoD, scored from 0 to 4, toxicity defined as ≥ 2 pt increase). The clinical data were fitted by the Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) NTCP models.
RESULTS
Of 55 evaluable patients, 19 (35%) had ≥ 20 point increase in xerostomia score, 11 (20%) had ≥ 2 point increase in xerostomia bother score, and 13 (24%) had ≥ 2 point increase in SESoD score. For xerostomia, parotid V-V correlated best with toxicity, with AUC 0.68 for xerostomia score and 0.69-0.71 for bother score. The values for the D, m and n parameters of the LKB model were 22.3 Gy, 0.84 and 1.0 for xerostomia score and 28.4 Gy, 0.55 and 1.0 for bother score, respectively. The corresponding values for the D, γ and s parameters of the RS model were 23.5 Gy, 0.28 and 0.0001 for xerostomia score and 32.0 Gy, 0.45 and 0.0001 for bother score, respectively. For dry eye, lacrimal V-V were found to correlate best with toxicity, with AUC values from 0.67 to 0.68. The parameter values of the LKB model were 53.5 Gy, 0.74 and 1.0, whereas of the RS model were 54.0 Gy, 0.37 and 0.0001, respectively.
CONCLUSIONS
Xerostomia was most associated with parotid V-V, and dry eye with lacrimal V-V. NTCP models were successfully created for both toxicities and may help clinicians refine dosimetric goals and assess levels of risk in patients receiving palliative WBRT.
Topics: Adult; Aged; Aged, 80 and over; Brain Neoplasms; Cranial Irradiation; Dose Fractionation, Radiation; Dose-Response Relationship, Radiation; Dry Eye Syndromes; Humans; Lacrimal Apparatus; Middle Aged; Organs at Risk; Parotid Gland; Probability; Prospective Studies; Radiation Injuries; Radiotherapy, Conformal; Risk Assessment; Xerostomia; Young Adult
PubMed: 33743773
DOI: 10.1186/s13014-021-01786-6 -
Journal For Immunotherapy of Cancer Jul 2022The use of low-dose irradiation (LDI) for mobilizing innate and adaptive immunity is gaining interest among the scientific community. Recent evidence suggests that LDI...
The use of low-dose irradiation (LDI) for mobilizing innate and adaptive immunity is gaining interest among the scientific community. Recent evidence suggests that LDI can reprogramme the tumor microenvironment, induce inflammation and turn cold tumors susceptible to immunecheckpoint blockade therapy. Translating immuno-radiation preclinical findings in the clinic is more challenging than expected. We propose therapeutic strategies for combining LDI with immunotherapy, and emphasize the importance of pursuing clinical research to determine optimal radiation dosage, fractionation, volumes, and sequencing to stimulate immune-mediated tumor responses.
Topics: Adaptive Immunity; Humans; Immunologic Factors; Immunotherapy; Neoplasms; Tumor Microenvironment
PubMed: 35835490
DOI: 10.1136/jitc-2022-004939 -
Pediatric Blood & Cancer May 2023Radiation therapy normal tissue dose constraints are critical when treating pediatric patients. However, there is limited evidence supporting proposed constraints, which... (Review)
Review
BACKGROUND
Radiation therapy normal tissue dose constraints are critical when treating pediatric patients. However, there is limited evidence supporting proposed constraints, which has led to variations in constraints over the years. In this study, we identify these variations in dose constraints within pediatric trials both in the United States and in Europe used in the past 30 years.
PROCEDURE
All pediatric trials from the Children's Oncology Group website were queried from inception until January 2022 and a sampling of European studies was included. Dose constraints were identified and built into an organ-based interactive web application with filters to display data by organs at risk (OAR), protocol, start date, dose, volume, and fractionation scheme. Dose constraints were evaluated for consistency over time and compared between pediatric US and European trials RESULTS: One hundred five closed trials were included-93 US trials and 12 European trials. Thirty-eight separate OAR were found with high-dose constraint variability. Across all trials, nine organs had greater than 10 different constraints (median 16, range 11-26), including serial organs. When comparing US versus European dose tolerances, the United States constraints were higher for seven OAR, lower for one, and identical for five. No OAR had constraints change systematically over the last 30 years.
CONCLUSION
Review of pediatric dose-volume constraints in clinical trials showed substantial variability for all OAR. Continued efforts focused on standardization of OAR dose constraints and risk profiles are essential to increase consistency of protocol outcomes and ultimately to reduce radiation toxicities in the pediatric population.
Topics: Humans; Child; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Organs at Risk; Dose Fractionation, Radiation; Radiation Injuries
PubMed: 36880707
DOI: 10.1002/pbc.30270